The invention relates to a sensor element for detecting at least one analyte in a body fluid or in a body tissue. The invention further relates to a sensor arrangement which comprises a sensor element according to the invention and an optical detector. The invention also relates to a method for generating a sensor element. Such sensor elements, sensor arrangements and methods are used in particular for determining at least one metabolite concentration in a body fluid and/or in a body tissue. Such metabolites can include by way of example, but not exclusively, blood glucose, lactate, cholesterol or other types of analytes and metabolites. Alternatively or in addition, however, the sensor element or the sensor arrangement can also be used in other fields of analysis, for example in the field of analytical chemistry, particularly in in situ analysis, process monitoring or in similar fields.
Conventional systems for determining analyte or metabolite concentrations are in many cases based on generating a sample of a body fluid, for example a drop of blood, which is then tested with respect to its analyte content by means of a suitable measurement appliance. For example, optical and/or electrochemical measurement methods can be used.
In order to reduce the inconvenience that patients experience in connection with the frequent generation of blood samples, various non-invasive or minimally invasive techniques have been developed for measuring analyte concentrations. Determination of the blood glucose concentration is discussed below without limiting the scope of protection of the invention, as it is of course also possible, alternatively or in addition to this, to detect other types of analytes and metabolites.
The invasive techniques for determining the analyte concentration are usually based on sensors which can be implanted into a body tissue and/or into a body fluid and which can determine the analyte concentration by optical and/or electrochemical means.
Optical systems generally use at least one sensor material which changes at least one optically measurable property in the presence of one or more specific analytes. This optically measurable property can take the most diverse forms, with many different methods, sensor materials and measurement devices being known from the prior art. In principle, all of these known sensor materials can also be used in the context of the present invention.
Thus, for example, WO 01/13783 describes an ocular sensor for glucose, which is designed as an ophthalmic lens. The ocular sensor comprises, as sensor material, a glucose receptor, which is marked with a first fluorescence label, and a glucose competitor, which is marked with a second fluorescence label (“donor”). The two fluorescence labels are chosen such that, when the competitor is bound to the receptor, the fluorescence of the second fluorescence label is quenched on account of a resonant fluorescence energy transfer. By monitoring the change in the fluorescence intensity at a wavelength around the fluorescence maximum of the quenchable fluorescence label, it is possible to measure the proportion of the fluorescence-marked competitor that has been displaced by the glucose. In this way, the glucose concentration in the eye fluid can be determined. The measurement can in turn be used to draw conclusions regarding the blood glucose concentration. Other types of detection are also conceivable and are familiar to persons skilled in the art, for example a fluorescence detection of the first fluorescence label.
WO 02/087429 describes a fluorescence photometer by means of which blood glucose concentrations can be determined by measuring the glucose concentrations from the eye fluid. The illustrated device is able to measure simultaneously two fluorescence intensities at different wavelengths.
However, a challenge that arises when using optical detection systems based on an optical sensor material in implanted sensors is of course that of conducting optical signals from a measuring appliance to the sensor material and/or in the reverse direction, i.e. from the sensor material to the measuring appliance. In the devices described in WO 01/13783 and WO 02/087429, this problem is of lesser importance, since the tissue layers that cover the implanted sensor are generally transparent in the region of the eye and thus permit coupling in and out of light signals. However, the technical challenge of optical coupling increases when sensors are implanted in non-transparent skin areas. The present invention is therefore not limited to use in the eye region and instead also includes the possibility of implantation in areas of the body where the implanted sensor is covered by non-transparent tissue parts.
To overcome the described problems of optical coupling, various systems are known from the prior art. Thus, for example, WO 2005/054831 A1 describes a sensor element for determining a glucose concentration, which uses an optical waveguide. A sensor element is applied to the distal end of the optical waveguide, which sensor element comprises a binding protein that can bind with at least one target analyte. The sensor element furthermore comprises at least one reporter group which is subject to a change in luminescence if the analyte concentrations change. The sensor element optionally comprises reference groups with luminescence properties that do not substantially change if the analyte concentrations change.
D. Meadows and J. S. Schultz: Fiber-optic biosensors based on fluorescence energy transfer, Talanta, vol. 35, no. 2, pages 145-150, 1988, describe a biochemical glucose-testing method based on a fluorescence energy transfer. Among other things, they propose the use of optical waveguides for coupling to a sensor element. The sensor element comprises a hollow dialysis fiber through which the analyte to be detected, in this case glucose, is able to diffuse and thus reach the sensor material located in the inside of the dialysis fiber.
U.S. Pat. No. 7,226,414 B2 describes a glucose sensor device to be implanted within the subcutaneous tissue of an animal body. A sensor material is arranged in a first chamber, with glucose being able to enter the first chamber from the body tissue. The sensor element further comprises a reference chamber with a reference solution. The use of optical waveguide fibers that connect a detection appliance to the chambers is once again proposed for coupling a read-out appliance thereto.
US 2007/0122829 A1 proposes a system, a device and a method for measuring the concentration of an analyte in a liquid or a matrix. A thermodynamically stabilized, analyte-binding ligand is proposed. In this case too, the use of a separate optical waveguide, which is in the form of a fiber and coupled to a sensor element, is again proposed, which optical waveguide connects a detection appliance to an implanted sensor element.
However, aside from the disclosed sensor materials, which can also be used for example in the context of the present invention, WO 2005/054831 A1, the publication by D. Meadows et al., U.S. Pat. No. 7,226,414 B2 and US 2007/0122829 A1 have considerable disadvantages in practice. One considerable disadvantage lies in the expensive production of such sensor elements, since the actual sensor element itself first has to be produced, after which it has to be connected to a suitable optical waveguide fiber, in order subsequently to implant this arrangement. Since optical waveguide fibers in practice have considerable sensitivity to mechanical loads, it can also happen that the optical waveguides are damaged during implantation, as a result of which the functionality of the sensor elements is adversely affected or indeed prevented. Moreover, in order to remove the sensor elements, including the optical fibers, it is sometimes necessary to perform considerable interventions in the body tissue, since pulling the optical waveguide fibers out of the body tissue generally causes detachment of the sensor element from the optical waveguide fiberfiber.